1,721,035 research outputs found
Staminali per la cura del tumore del pancreas: tra evidenze scienti che e possibile trasferimento clinico
No full textUna nuova promessa terapeutica arriva dall'utilizzo di cellule umane ca- paci di indurre la morte delle cellule tumorali tramite il rilascio di composti tossici
Surrounding pancreatic adenocarcinoma by killer mesenchymal stromal/stem cells
No full textN/ADepicting the strong interaction with genetically modified stem cells and few pancreatic adenocarcinoma lines, authors here suggest adult stem cells as suitable vectors for anti-cancer agents delivery opening novel therapeutic opportunities for this still incurable cancer
METHOD FOR PRODUCTION OF ANTI-TUMOR TRAIL PROTEIN
No full textThe method for production of anti-tumor TRAIL comprises: inserting a TRAIL molecule, encoded by a viral vector irreversibly derived from a cell line, into a carrier cell, thereby obtaining a stably TRAIL-producing carrier cell, said TRAIL molecule comprising a soluble molecule
Combination of low doses of Enzastaurin and Lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines
No full textLess toxic and more active treatments are needed for indolent lymphomas as there is no curative treatment, and patients eventually die due to complications related to their disease. The purpose of the present study was to assess the antitumour activity of the combination of low doses of Enzastaurin and Lenalidomide (Revlimid) on B-lymphoma cell lines. The combination of Enzastaurin and Lenalidomide, at doses as low as 1 μM, showed strong synergism against indolent lymphomas by reducing cell growth, producing an increase in G0-G1 phase followed by significant decrease in S phase, increasing apoptosis, and inhibiting PI3K/AKT, PKC and MAPK/ERK pathways. These preclinical findings, together with promising results obtained with Lenalidomide for the treatment of non-Hodgkin lymphoma, suggest that further evaluation of the combination of Enzastaurin and Lenalidomide for the treatment of indolent lymphomas is warranted. These compounds, with a favourable toxicity profile, are not classic chemotherapeutic agents, causing severe side effects, and could be considered an example of a new innovative attempt of an anti-cancer 'soft treatment'
An adoptive immuno-gene therapy approach targeting neuroblastoma.
No full textAlthough dose intensification of chemotherapy has increased initial response rates in neuroblastoma (NB), this effect has not translated into durable remissions in patients with disseminated disease. Immunotherapy may be an alternative approach following cytoreductive chemotherapy providing a long-term disease control (I).
We have engineered human cytotoxic T lymphocytes (CTL) to express a chimeric receptor (CR) for the specific recognition of GD2 that is expressed in NB (II). Chimeric lymphocytes (CL) have been previously introduced towards several tumors (III). Thus, we have generated a novel CR consisting of a single-chain variable domain of an anti-GD2 antibody in conjunction with a signal domain of 4-1BB molecule (CD137).
Retroviral particles encoding for the flag gene only (GFP), for the whole CR and for a truncated receptor were generated. Peripheral blood cells from buffy-coat were specifically stimulated and transuced obtaining a cytotoxic population of T cells having high level of transduction (50±25%). Co-culture experiments were then performed against NB cell lines. In short (4h) co-culture experiments (T:E=1:20) by Cr51 release assay, CLs exerted a powerful and specific cytotoxicity against GD2-positive NB cells, compared with truncated controls (35±5% and 10,8±4% ; p<0,05). Moreover, in a longer co-culture assay (5 days) in vitro at higher ratio (T:E =1:5), using as read-out FACS analyses targeting GD2 expressing cells, we observed a significant decrease (from 92±3% to 19±5% ; p<0.05) of the NB cells compared with controls (from 92±3% to 76,5±4% %; p<0.05). These preliminary data in vitro suggest that CL against GD2-positive NB cells may represent a powerful new tool for T-cell therapy in patients with GD2-positive NB or other GD2-positive malignancies
Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells
No full textThe tumor microenvironment plays an important role in cancer progression. Here, we focused on the role of reactive mesenchymal stem cells (MSC) in osteosarcoma (OS), and used human adipose MSC and a panel of OS cell lines (Saos-2, HOS, and 143B) to investigate the mutual effect of normal-cancer cell metabolic programming. Our results showed that MSC are driven by oxidative stress induced by OS cells to undergo Warburg metabolism, with increased lactate production. Therefore, we analyzed the expression of lactate monocarboxylate transporters. By real time PCR and immunofluorescence, in MSC we detected the expression of MCT-4, the transporter for lactate efflux, whereas MCT-1, responsible for lactate uptake, was expressed in OS cells. In agreement, silencing of MCT-1 by siRNA significantly affected the ATP production in OS cancer cells. Thus, cancer cells directly increase their mitochondrial biogenesis using this energy-rich metabolite that is abundantly provided by MSC as an effect of the altered microenvironmental conditions induced by OS cells. We also showed that lactate produced by MSC promotes the migratory ability of OS cells. These data provide novel information to be exploited for cancer therapies targeting the mutual metabolic reprogramming of cancer cells and their stroma.The tumor microenvironment plays an important role in cancer progression. Here, we focused on the role of reactive mesenchymal stem cells (MSC) in osteosarcoma (OS), and used human adipose MSC and a panel of OS cell lines (Saos-2, HOS, and 143B) to investigate the mutual effect of normal-cancer cell metabolic programming. Our results showed that MSC are driven by oxidative stress induced by OS cells to undergo Warburg metabolism, with increased lactate production. Therefore, we analyzed the expression of lactate monocarboxylate transporters. By real time PCR and immunofluorescence, in MSC we detected the expression of MCT-4, the transporter for lactate efflux, whereas MCT-1, responsible for lactate uptake, was expressed in OS cells. In agreement, silencing of MCT-1 by siRNA significantly affected the ATP production in OS cancer cells. Thus, cancer cells directly increase their mitochondrial biogenesis using this energy-rich metabolite that is abundantly provided by MSC as an effect of the altered microenvironmental conditions induced by OS cells. We also showed that lactate produced by MSC promotes the migratory ability of OS cells. These data provide novel information to be exploited for cancer therapies targeting the mutual metabolic reprogramming of cancer cells and their stroma
Effects of Enzastaurin, Alone or in Combination, on Signalling Pathway Controlling Growth and Survival of B-Cell Lymphoma Cell LinesBlood (ASH Annual Meeting Abstracts), Nov 2008; 112: 4978
No full textBackground. Although, the recent introduction of Rituximab in combination with chemotherapy has improved outcome of patients with indolent lymphomas, in particular FL, these diseases are still considered incurable and the majority of patients still have a fatal course. Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective competitive inhibitor of protein kinase C beta, which has been shown to inhibit cell proliferation and angiogenesis in human cancer cell lines. The purpose of the present study was to test enzastaurin for its effects on proliferation and survival of B-cell lines established from NHL patients. Methods. The WSU-NHL and Karpas 422 were kindly provided Dr M Introna ( Division of Haematology, Ospedali Riuniti, Bergamo, Italy); the RL was purchased by DSMZ. All three lines are carrying the t(14; 18) and Karpas 422 is EBV+. We decided to conduct all the experiments under the optimal culture conditions with 10% FCS to avoid subjecting the cells to further stress stimuli. IC50 values were calculated from curves based on enzastaurin concentration ranging from 1 to 10μM using MTT assay and cell viability assessment by Trypan Blue exclusion. Cell apoptosis was assessed by flow cytometer after staining with Annexin V-FITC and propidium iodide. The effects of enzastaurin on caspases activation as well as on AKT phosphorilation were evaluated by Western blotting. We also investigated the interaction of enzastaurin with chlorambucil and fludarabine. Results using MTT assay were expressed as fraction of cells killed by the individual drug or the combination in the drug-treated versus untreated cells. The interaction between drugs was analyzed by isobologram analysis using the StaCorp8.2 software program based upon the Chou-Talalay method to determine if the combinations were additive or synergistic. Results. We found that enzastaurin alone inhibits the proliferation of B-cell lymphomas cell lines at IC50 values ranging from 5 to 7.5 μM after 48 h and from 2.5 to 3.2 μM after 72 h. Induction of apoptosis by enzastaurin evaluated on WSU-NHL and RL, by flow cytometry analysis of membrane permeability, showed that enzastaurin induces an increase in the percentage of apoptotic cells compared with untreated controls in a time-dependent fashion. Furthermore, enzastaurin induces the appearance of the cleaved caspase-3 fragment in the same cell lines in a time dependent fashion. Activation of the apoptotic pathway was confirmed by cleavage of the PARP enzyme. The apoptosis is partially prevented by the ZVAD–fmk broad caspase inhibitor. Phosphorilation status analysis of AKT up to 72h of treatment showed a decrease of AKT phosphorilation starting from 48h after treatment. We tested the effect of enzastaurin combined with chlorambucil and fludarabine,drugs that are active against B-cell lymphoma and we demonstrated that these agents enhanced the cytotoxicity triggered by enzastaurin in a dose-dependent fashion. A clear synergistic interaction (CI=0.87) appeared using low concentrations of the drugs and increased (CI=0.1) at high concentrations. Conclusions. Our data suggest that in B lymphoma cell lines carrying t(14; 18), enzastaurin elicits its antitumor effect suppressing AKT phosphorilation, inducing apoptosis and inhibiting proliferation. Furthermore, enzastaurin synergizes with chlorambucil and fludarabine. These results support the potential use of enzastaurin in patients with NHL, and in particular provide a rationale for combination with chlorambucil and fludarabin
Sarcomas as a mise en abyme of Mesenchymal Stem Cells; exploiting interrelationships for cell mediated anticancer therapy
No full textMise en abyme meaning "placed into abyss or infinite recurrence" is an apt paradigm for the relentless growth of sarcoma cells. Its alternative meaning, "self-reflexive embedding" fits the central role attributed to cancer stem cells (CSCs). Diversely sourced and defined, mesenchymal stem cells (MSCs) may be the cells of sarcoma origin, evolve a CSC phenotype and/or contribute to tumor growth through inherent qualities for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, cell fusion, entosis and immune modulation. Exploiting these qualities, MSC expressing modified forms of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) are being developed to complement more conventional radiation and chemotherapy
CD271 downregulation promotes melanoma progression and invasion in 3-dimensional models and in zebrafish
Full text linkCD271 is a neurotrophin receptor variably expressed in melanoma. While contradictory data are reported on its role as a marker of tumor initiating cells, little is known on its function in tumor progression. CD271 expression was higher in spheroids derived from freshly isolated cells of primary melanomas and in primary WM115 and WM793-B cell lines, while it decreased during progression to advanced stages in cells isolated from metastatic melanomas and in metastatic WM266-4 and 1205Lu cell lines. Moreover, CD271 was scarcely detected in the highly invasive spheroids (SKMEL28 and 1205Lu). CD271, originally expressed in the epidermis of skin reconstructs, disappeared when melanoma started to invade the dermis. SKMEL8 CD271(-) cells showed greater proliferation and invasiveness in vitro, and were associated with a higher number of metastases in zebrafish, as compared to CD271(+) cells. CD271 silencing in WM115 induced a more aggressive phenotype in vitro and in vivo. On the contrary, CD271 overexpression in SKMEL28 cells reduced invasion in vitro, and CD271 overexpressing 1205Lu cells was associated with a lower percentage of metastases in zebrafish. A reduced cell-cell adhesion was also observed in absence of CD271. Taken together, these results indicate that CD271 loss is critical for melanoma progression and metastasis
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